tbuckley/cabot-search huggingface dataset:
DISP-14. DEFINING INTERVENTIONS AND METRICS TO IMPROVE DIVERSITY IN CNS CLINICAL TRIAL PARTICIPATION: A SNO AND RANO EFFORT
Authors: Joshua Budhu, Alyx Porter, Sadhana Jackson, Eudocia Lee, J Ricardo McFaline-Figueroa, Nicole Willmarth, Mahalia Dalmage, Ichiro Kawachi, David Arons, Susan M Chang, Patrick Y Wen, Shawn L Hervey-Jumper, Ugonma Chukwueke
Journal: Neuro-Oncology (2022)

Abstract Despite major strides in cancer research, care, and therapy, these advances have not been equitable across race and ethnicity. Groups underrepresented in medicine (URM) are more likely to have inadequate preventive screening, increased delays in diagnosis, and poor representation in clinical trials. Notably, Black and Latino Americans represent 29% of the population but only reflect 8% of oncology clinical trial participants. Recent studies have shown that this disparity is also present in neuro-oncology as women, Black, and Latino Americans remain under-accrued in clinical trials. Brain tumor patients already face unique barriers to clinical trial enrollment and completion due to disease-specific conditions–such as impaired motor function, cognition, language deficits, and caregiver dependency–which pose additional difficulties in clinical trial consent, enrollment, and adherence. As part of this collaborative initiative, we evaluated the impact of how a lack of diversity in cancer research is detrimental to scientific discovery and propose interventions focused on improving URM engagement with clinical research. Recommendations include the creation of inclusive trial design at the onset, decreasing barriers to care, expanding trial eligibility, and equitable access to tumor profiling for personalized medical trials. Additionally, setting reasonable metrics and goals for accrual and engagement with patient and community stakeholders will ultimately help to diversify trial participants. Lastly, diversification and inclusion practices within the neuro-oncology workforce, including all personnel involved in clinical research, will help to minimize bias, promote concordant care, and assist with developing sustainable solutions. The diversification of participation in neuro-oncology clinical trials is imperative. The lack of diversity in clinical trials can contribute to improper generalizability of treatment efficacy, resulting in potentially harmful practices. Equitable access and inclusion of URM brain tumor patients will not only enhance research discoveries but will also result in improved patient care for all cancer patients.
EPCO-43. CHROMATIN REMODELERS LOST IN TRANSLATION
Authors: Capucine Van Rechem
Journal: Neuro-Oncology (2022)

Abstract The chromatin remodeler complexes mammalian SWI/SNF (SWItch/Sucrose Non-Fermentable) are altered in more than 40% of cancers and are involved in therapeutic resistance. In children,SMARCB1 is mutated in 95% of rhabdoid tumors, and the remaining 5% present mutations in SMARCA4. These tumors are typically identified in children younger than three years old and have a very poor prognosis with a survival under one year following diagnosis. SMARCB1 expression is also lost in more than 90% of epithelial sarcomas, a rare and aggressive tumor affecting young adults, and in 50% of pediatric chordomas. Additional mSWI/SNF subunits are also highly mutated in childhood cancers such as ARID1A and ARID1B in neuroblastomas, the most common solid tumor in children, and the ARID subunits and SMARCA4 in medulloblastomas, the most common brain cancer in children. To date, mSWI/SNF roles in normal and cancer cells are still largely undetermined and focus on nuclear functions. However, our assessment of genetic dependencies and drug sensitivity screens revealed that cancer cells mutated for mSWI/SNF are genetically dependent and exclusively sensitive to translation factors and translation pathway inhibitors. We demonstrate that mSWI/SNF complexes are extensively localized in the cytoplasm and that they interact with the translation initiation machinery. Furthermore, short-term inhibition, depletion and cancer mutations of specific subunits alter protein synthesis and increase sensitivity to translation inhibitors. Most mutations in these complexes being considered loss of function, these results suggest a potential therapeutic opportunity for diseases presenting mutations in these complexes. In conclusion, our work demonstrates the chromatin remodelers mSWI/SNF have direct roles in translation that will not only be relevant for the molecular understanding of cancer but also lead to new therapeutic opportunities.
DDDR-39. IDENTIFICATION OF A NOVEL THERAPEUTIC TARGET THAT IS SYNTHETICALLY LETHAL WITH MUTANT IDH INHIBITOR IN GLIOMA USING THE CRISPR/CAS9 GENOME EDITING TECHNOLOGY
Authors: Sachi Maeda, Kosuke Aoki, Kunihiko Hinohara, Junya Yamaguchi, Fumiharu Ohka, Kazuya Motomura, Yuji Kibe, Atsushi Natsume, Ryuta Saito
Journal: Neuro-Oncology (2022)

Abstract Diffuse glioma is the most frequent and malignant neuroepithelial tumor in the central nervous system. IDH mutations are the most frequent genetic mutations in adult gliomas. The WHO Classification of Tumors, 5th edition, volume 6: Central Nervous System Tumours revised in 2021, defines the presence of IDH mutations in gliomas as astrocytoma IDH-mutant and oligodendroglioma IDH-mutant and 1p/19q-codeleted. In addition, more than 90% of IDH mutations found in gliomas are IDH1 R132H mutation. Several clinical trials of mutant IDH1 inhibitors targeting the IDH1 R132H mutation have shown their efficacy, but it has also been reported that IDH1 inhibitors alone may not provide sufficient tumor suppression. In this study, we performed genome-wide knockout screening using CRISPR/Cas9 genome editing technology to search for new drug targets that are synergistic with the mutant IDH1 inhibitor DS-1001b. The results of CRISPR screening and RNA sequence analysis revealed that several metabolism-related genes are factors that define resistance to mutant IDH inhibitor. In a tumor suppression study, treatment of two IDH1 R132H mutant glioma cell lines (MGG152 and BT142) with mutant IDH1 inhibitor suppressed production of the oncometabolite D2-HG, but did not significantly alter cell growth. However, when mutant IDH1 inhibitor were combined with inhibitor for metabolism-related genes, cell survival was significantly reduced, and the effects were synergistic. In this study, we found that administration of mutant IDH inhibitors to IDH mutant gliomas significantly altered intratumor metabolism using various molecular approaches. We then identified targets that, when combined with mutant IDH inhibitor, provide synergistic tumor suppression. These results are expected to provide a new therapeutic approach for a subset of patients who have difficulty responding to mutant IDH1 inhibitors.
DDDR-29. THE HYDROGEL-CXCL9-MRNA (HCM) VACCINE RESULTS IN SIGNIFICANT ANTI-TUMOR EFFICACY THROUGH RECRUITMENT OF NATURAL KILLER (NK) CELLS
Authors: Farhad Dastmalchi, Nagheme Thomas, Ghaidaa Ebrahim, Matt Frain, Ginger Moore, Hector Mendez-Gomez, Elias Sayour, Macaulay Tomdio, Vignesh Subramaniam, Thomas Angelini, Duane Mitchell, Maryam Rahman
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Immunotherapy for GBM has resulted in limited benefits to overall survival due to the targeting of limited antigens and the hostile TME. Our group has developed a patented vaccine platform that combines an mRNA-nanoparticle with CXCL9 loaded polyethylene glycol (PEG) hydrogel. The HCM vaccine is given SQ and recruits a diverse immune cell population to deliver a large payload of mRNA. The objective of these studies was to evaluate the efficacy and mechanisms of action of the HCM vaccine. METHODS: C57BL/6 mice underwent intracranial implantation of KR158 glioma cells. The HCM vaccine was formulated with total tumor mRNA, DOTAP, CXCL9 and PEG hydrogel created in collaboration with the College of Engineering. Survival studies were analyzed with the Mantel-Cox test. Flow cytometry and ELISA data was analyzed using ANOVA. Graphpad was used for statistical analysis. RESULTS: KR158-glioma intracranial tumor bearing mice were treated with SQ injection of the HCM vaccine (total tumor mRNA, DOTAP, CXCL9, PEG hydrogel). KR158 tumor bearing animals are resistant to treatment with radiation, temozolomide and other immunotherapy platforms in our laboratory. Treatment animals lived significantly longer compared to control animals (35 days versus 22 days, p &amp;lt; 0.0001). In a separate experiment, the fat pad was collected after vaccination and flow cytometry revealed recruitment of dendritic cells (DCs), CD4 and CD8 T cells and NK cells. Large numbers of antigen specific CD8 T cells were found in the spleen and within the TME after vaccination. When NK cells were blocked (NK 1.1 blocking antibody), the survival benefit from the vaccine was completely abrogated. NK cells were found to increase antigen presentation and available IFN-gamma within the PEG hydrogel scaffold. CONCLUSION: The HCM vaccine demonstrates efficacy in resistant murine glioma models and the efficacy is dependent on recruitment of NK cells at the site of vaccination.
IMMU-15. HUMAN ALLOGENIC γδ T CELLS KILL PATIENT-DERIVED GLIOBLASTOMA CELLS IN A PVR- AND DNAM-1-DEPENDENT MANNER
Authors: Stephen Ahn, Haeyoun Choi
Journal: Neuro-Oncology (2022)

Abstract Background Adoptive transfer of γδ T cells is a novel immunotherapeutic approach to glioblastoma. Few recent studies have shown the efficacy of γδ T cells against glioblastoma, but no previous studies have identified the ligand–receptor interactions between γδ T cells and glioblastoma cells. Here, we identify those ligand–receptor interactions and provide a basis for using γδ T cells to treat glioblastoma. METHODS Vγ9Vδ2 T cells were generated from peripheral blood mononuclear cells of healthy donors using artificial antigen presenting cells. MICA, ULBP, PVR and Nectin expression in 10 patient-derived glioblastoma (PDG) cell lines were analyzed. The in vitro cytokine secretion from the γδ T cells and their cytotoxicity toward the PDG cell lines were also analyzed. The in vivo anti-tumor effects were evaluated using a U87 orthotopic xenograft glioblastoma model. RESULTS Expression of ligands and cytotoxicity of the γδ T cells varied among the PDG cell lines. Interestingly, cytotoxicity correlated significantly with the PVR expression of the PDG cells. IFN-γ and granzyme B secretion levels were significantly higher when γδ T cells were co-cultured with high PVR–expressing PDG cells than when they were co-cultured with low PVR–expressing PDG cells. Blocking DNAM-1 resulted in a decrease in γδ T cell–mediated cytotoxicity and cytokine secretion. Intratumoral injection of γδ T cells showed anti-tumor effects in an orthotopic mouse model. Conclusions Allogenic γδ T cells showed potent anti-tumor effects on glioblastoma in a PVR- and DNAM-1-dependent manner. Our findings will facilitate the development of clinical strategies using γδ T cells for glioblastoma treatment.
EPID-05. LEPTOMENINGEAL METASTASES IN GLIOMA REVISITED: HIGH INCIDENCE AND THEIR MOLECULAR PREDICTORS BASED ON RECENT IMAGING AND MOLECULAR DIAGNOSTICS
Authors: Yae Won Park, Sung Soo Ahn, Jong Hee Chang, Se Hoon Kim, Seung-Koo Lee
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Leptomeningeal metastases (LM) in glioma has been underestimated due to low incidence and lack of reliable imaging. This study aimed to investigate a real-world incidence of LM using a CSF-sensitive MR imaging technique and analyze molecular predictors for LM in the molecular era. METHODS Total 1,405 adult glioma patients underwent post-contrast fluid attenuated inversion recovery (FLAIR) imaging at initial diagnosis and during treatment monitoring between March 2001 and October 2021. Molecular data included isocitrate dehydrogenase (IDH) mutation, 1p/19q co-deletion, H3 K27M alteration, and O6-methylguanine-methyltransferase (MGMT) promoter methylation status. Multivariable logistic regression analysis for LM development was performed in molecular data, clinical data, and imaging characteristics. Median overall survival (OS) was compared between patients with and without LM using Kaplan-Meier survival curves and log-rank test. RESULTS LM was identified in 16.2% of glioma (228 of 1405), with 7.8% (110 of 1405) at initial diagnosis, and 8.4% (118 of 1405) at recurrence. Among molecular diagnostics, IDH-wildtype (odds ratio [OR] 3.14, P = .001) and MGMT promoter unmethylation (OR 1.43, P = .034) were independent predictors of LM. WHO grade 4 (OR 10.52, P &amp;lt; .001) and nonlobar location (OR 1.54, P =.048) were associated with LM at initial diagnosis, whereas IDH-wildtype (OR 5.04, P &amp;lt; .001) and H3 K27M alteration (OR 3.39, P =.003) were significantly associated with LM at recurrence. Patients with LM had a worse median OS than those without LM (16.7 vs. 32.0 months, log-rank test; P &amp;lt; .001). CONCLUSIONS CSF-sensitive MR imaging diagnostics aid diagnosis of LM and reduced an underdiagnosed condition in adult gliomas. Molecular markers affect LM at initial diagnosis and at recurrence, and patients with aggressive molecular markers warrant imaging surveillance of LM.
EPID-22. MATERNAL USE OF TOBACCO, ALCOHOL, AND ILLICIT DRUGS DURING PREGNANCY AND ASSOCIATION WITH CHILDHOOD CANCER SUBTYPES
Authors: Courtney Wimberly, Natalie Gulrajani, Lisa Towry, Daniel Landi, Kyle Walsh
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE To investigate the association between maternal prenatal substance use/abuse and diagnosis of childhood cancer subtypes, including childhood brain tumors. To minimize recall bias, we employed a case-only study design in which all respondents had a child diagnosed with cancer. STUDY DESIGN: We deployed a cross-sectional, case-only survey of parents of children diagnosed with cancer regarding prenatal smoking, drinking, and illicit drug use behaviors (scored on 1-7 Likert scale), demographic, gestational, and perinatal factors. Multivariable logistic regression assessed associations of gestational smoking, alcohol, and illicit drug use with childhood cancer subtypes, adjusting for child sex, race/ethnicity, birthweight, and household income. RESULTS 3145 families completed the survey, including 232 with astrocytoma (grades I-IV, including DIPG) and 210 with an embryonal CNS tumor (medulloblastoma, AT/RT, PNET). A minority reported ever smoking tobacco products during pregnancy (Likert score ≥ 2; 14%), ever consuming illicit drugs during pregnancy (Likert score ≥ 2; 4%), or drinking more than a moderate amount of alcohol during pregnancy (Likert score ≥ 5; 2%). Prenatal smoking was associated with lower odds of rhabdomyosarcoma (OR=0.48, P=0.023) and moderately elevated odds of non-Hodgkin lymphoma (OR = 1.52, P=0.098) and AML (OR = 1.52, P = 0.083). Moderate to heavy alcohol consumption was unassociated with cancer subtypes. Prenatal illicit drug use was associated with increased odds of retinoblastoma (OR = 5.03, 95% CI = 1.73-14.7, P = 0.003) and CNS embryonal tumors (OR = 2.56, 95% CI = 1.32-4.99, P = 0.006), with similar effects across subgroups of medulloblastoma, AT/RT, and supratentorial PNETs. CONCLUSIONS Associations between self-reported use of alcohol, tobacco, and illicit drugs during pregnancy and risk of childhood cancer is often biased by differential misreporting among parents of affected children. Consistent with prior reports, we observe elevated odds of hematologic malignancies in association with gestational tobacco smoke exposure and novel association between maternal illicit drug use during pregnancy and elevated odds of retinoblastoma and CNS embryonal tumors.
IMMU-07. HUMANIZED BI-SPECIFIC ANTIBODY SHOWS POTENT ACTIVITY IN PATIENT-DERIVED XENOGRAFT MODELS OF GLIOBLASTOMA
Authors: Joseph Duffy, Markella Zannikou, Rebecca Levine, Roger Stupp, David James, Irina Balyasnikova
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Advancements in bioengineering have allowed bispecific Abs to develop with therapeutic applications in immuno-oncology. Here we describe a fully humanized bispecific t cell engager (BiTE) that binds the GBM-associated antigen interleukin 13 receptor alpha 2 (IL13Rα2) and the T Cell receptor CD3 epsilon (CD3ε) to elicit an anti-tumor immune response in patient-derived models of GBM. METHODS In vitro, BiTE-mediated activation of T Cells was assessed via flow cytometry as measurements of T cell activation markers CD25 and CD69 and cytokines IFNγ and TNFα. BiTE-directed T cell-mediated cytotoxicity was assessed in GBM 6 and GBM12patient-derived xenograft lines. In vivo, GBM6 patient-derived xenograft cells were intracranially implanted in NSG-MHC I/II DKO mice, reconstituted with HLA-matched donor peripheral blood lymphocytes (PBMC), and subsequently treated with 2.5 mg/kg BiTE via i.p. injection x 4 days/week of therapeutic BiTE for three weeks. Animals were followed for survival, and the brains of long-term survivors were analyzed for residual disease and T cell infiltration. RESULTS In vitro, BiTE potently activated T cells as determined by a high expression of CD25 and CD69 and the production of TNFα and IFNγ. BiTE also directed T cell-mediated cytotoxicity against GBM cells in a dose-dependent manner, with significant activity still seen in the low nanogram range. In vivo, BiTE significantly extended the survival of tumor-bearing animals in GBM6patient-derived xenograft models. Histological analysis of long-term surviving mice shows complete absence of tumor and robust presence of CD8+ T cells localized to the original site of tumor implantation. CONCLUSIONS Our data demonstrate the efficacy of humanized BiTE in patient-derived GBM models, and our results support the investigation of this novel therapeutic in a clinical trial setting.FUNDING: R01 NS122395-01 and R01 NS095642-01
BIOM-42. A DEEP LEARNING MODEL FOR AUTOMATED DETECTION AND COUNTING OF TUNNELING NANOTUBES AND CANCER CELLS IN MICROSCOPY IMAGES
Authors: Yasin Ceran, Hamza Ergüder, Katherine Ladner, Sophie Korenfeld, Karina Deniz, Sanyukta Padmanabhan, Murat Baday, Thomas Pengo, Emil Lou, Chirag Patel
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Tunneling nanotubes (TNTs) are cellular structures connecting cell membranes and mediating intercellular communication. TNTs are manually identified and counted by a trained investigator; however, this process is time-intensive. We therefore sought to develop an automated approach for quantitative analysis of TNTs. METHODS We used the convolutional neural network (U-Net) deep learning model to segment phase contrast microscopy images of both cancer and non-cancer cells. Our method was composed of preprocessing and model development. We developed a new preprocessing method to label TNTs on a pixel-wise basis. Two sequential models were employed to detect TNTs. First, we identified the regions of images with TNTs by implementing a classification algorithm. Second, we fed parts of the image classified as TNT-containing into a modified U-Net model to estimate TNTs on a pixel-wise basis. RESULTS The U-Net model detected 73.3% of human expert-identified TNTs, counted TNTs and cells, and calculated the TNT-to-cell ratio (TCR). We obtained a precision of 0.88, recall of 0.67, and f-1 score of 0.76 on a test data set. The predicted and true TCRs were not significantly different between the training and test data sets. CONCLUSIONS In summary, we report application of an automated model generated by deep learning and trained to accurately label and detect TNTs and cells imaged in culture. Continued application and refinement of this process will provide a new approach to the analysis of TNTs, which form to connect cancer and other cells. This approach has the potential to enhance the drug screens intended to assess therapeutic efficacy of experimental agents, and to reproducibly assess TNTs as a potential biomarker of response to therapy in cancer.
EPCO-25. MULTI-OMIC ANALYSIS OF THE GLIOBLASTOMA EPIGENOME AND TRANSCRIPTOME INFORMS OF MIGRATORY INTERNEURON-LIKE DEVELOPMENTAL REGULATORS
Authors: Susana Isabel Ramos, Zarmeen Mussa, Bruno Giotti, Alexander Tsankov, Nadejda Tsankova
Journal: Neuro-Oncology (2022)

Abstract Recent studies have demonstrated that, despite their nomenclature, gliomas recapitulate an interneuron progenitor-like state that drives tumor progression. During human neurodevelopment, interneurons arise from the subcortical ganglionic eminences and migrate tangentially into the neocortex, settling in the cortical plate where they integrate local neurocircuitry. Analogously, malignant glioblastoma (GBM) cells migrate from the tumor core into the surrounding healthy tissue. This innate infiltrative property renders these malignant cells elusive to surgical resection, leading to tumor recurrence. To understand the regulatory networks that drive tumor infiltration from a neurodevelopmental perspective, we generated a single-nucleus Assay for Transposase-Accessible Chromatin sequencing (snATAC-seq) dataset of 41,000 nuclei from the core and infiltrative edge of surgically resected GBM specimens (n = 4). Concurrently, we sequenced 46,000 nuclei from non-pathological, postmortem samples of second- and third-trimester neocortices (n = 17). We integrated these datasets with paired single-nucleus RNA sequencing (snRNA-seq) data and identified candidate regulatory TFs that exhibit high correlation between motif enrichment and TF expression. Using single-trajectory inference and pseudo-time analyses, we identified TCF12 as a potential driver of interneuron lineage fate in developing cortical progenitors. Given its implication in projection neuron migration, we were intrigued to find that TCF12 activity is highest in GBM cells with a migratory interneuron signature, hinting at its putative role in tumor infiltration. To understand the significance of these findings, we will interrogate other genes in the TCF12 regulatory network with the ultimate goal of identifying therapeutic targets that inhibit GBM infiltration.